1. ABSTRACT Fibromyalgia (FM) pain affects upwards of 5 million people in US annually and can have a considerable impact on patients? quality of life and costs for the society (e.g., treatments or unemployment costs). Given the limited and variable effects of most of the therapeutic interventions for FM, there is an unmet clinical need for the development of novel interventions in FM. Recent evidence has suggested that FM pain can be related to deficits in pain endogenous regulatory control. In this context, our central hypothesis is that, to improve their efficacy, novel treatments of FM need to target specific neural networks associated with this endogenous pain regulatory system. Our rationale is based on studies showing that transcranial direct current stimulation (tDCS) of primary motor cortex is a powerful non-invasive neuromodulation technique of known to significantly modulate neural plasticity and alleviate chronic pain. Our group reported the first positive results of tDCS in FM in 2006. In order to optimize the treatment effects of motor cortex tDCS, we recently hypothesized that combining tDCS with aerobic exercise (AE) would increase its effects, given its enhanced modulatory effect of motor system engagement on endogenous pain system by combining two therapies. We conducted a preliminary trial testing this hypothesis and showed a beneficial effect of the combined treatment. This proposal was developed based on this preliminary data. Our specific aims are: (i) evaluate the effects of tDCS and aerobic exercise on endogenous pain control as assessed by temporal slow pain summation (TSPS) and conditioned pain modulation (CPM); (ii) determine the effect of these interventions on cortical markers of inhibitory control that are also affected in FM, such as intracortical inhibition as assessed by transcranial magnetic stimulation (TMS) and changes in thalamocortical dysrhythmia as assessed by EEG; (iii) assess whether engagement of the two main targets tested in this study ? STS and CPM ? are associated with changes in pain outcomes (e.g., Brief Pain Inventory and other clinical scales). Our main approach will be carried out using a randomized 2x2 mechanistic factorial controlled trial in 94 patients diagnosed with FM. Subjects will be randomized to one of four groups: tDCS and AE; sham tDCS and AE; active tDCS and nAE (non-AE= control intervention for AE); sham tDCS and nAE. The findings from this study will be significant as there is an unmet clinical need for the development of novel therapies in FM, particularly non-pharmacological ones, based on mechanistic approaches and target engagement. The extensive sensory and electrophysiological measurements that will be conducted with conditioned pain modulation and temporal slow pain summation, single- and paired-pulse transcranial magnetic stimulation, and quantitative electroencephalography will provide novel mechanistic insights that, independently of the main clinical aim, will be significant to future studies investigating novel pain therapies. Current treatments for FM have either limited efficacy or are associated with systemic adverse effects. From a clinical perspective, as secondary analysis, we will investigate the time evolution of pain scores (i.e., BPI) to understand the treatment dose-response in order to provide important insights for the design of future trials investigating the analgesic effects of tDCS. Finally, this proposal is novel given that this treatment is based on a neural target for pain control, the endogenous pain control system, and the results of this trial will not only bring a potential novel way of treating FM, by looking into the endogenous pain control, but will also shed light into pain mechanisms of FM and its relationship to a major modulator: the motor system.